CX-5461 Sensitizes DNA Damage Repair–proficient Castrate-resistant Prostate Cancer to PARP Inhibition

Abstract

Monotherapy with PARP inhibitors is effective for the subset of castrate-resistant prostate cancer (CRPC) with defects in homologous recombination (HR) DNA repair. New treatments are required for the remaining tumors, and an emerging strategy is to combine PARP inhibitors with other therapies that induce DNA damage. Here we tested whether PARP inhibitors are effective for HR-proficient CRPC, including androgen receptor (AR)-null tumors, when used in combination with CX-5461, a small molecule that inhibits RNA polymerase I transcription and activates the DNA damage response, and has antitumor activity in early phase I trials. The combination of CX-5461 and talazoparib significantly decreased in vivo growth of patient-derived xenografts of HR-proficient CRPC, including AR-positive, AR-null, and neuroendocrine tumors. CX-5461 and talazoparib synergistically inhibited the growth of organoids and cell lines, and significantly increased the levels of DNA damage. Decreased tumor growth after combination therapy was maintained for 2 weeks without treatment, significantly increasing host survival. Therefore, combination treatment with CX-5461 and talazoparib is effective for HR-proficient tumors that are not suitable for monotherapy with PARP inhibitors, including AR-null CRPC. This expands the spectrum of CRPC that is sensitive to PARP inhibition.

Co‐targeting BET, CBP, and p300 inhibits neuroendocrine signalling in androgen receptor‐null prostate cancer

“…Establishment and treatment of patient-derived xenografts (PDXs) [22][23][24][25] and grown in male NSG mice. PDXs of castrate-sensitive prostate cancer were grown in mice supplemented with 5-mm testosterone implants, whereas PDXs of CRPC were grown in castrated host mice, as previously described [26][27][28][29][30][31][32].…”

“…All animal care was in accordance with Monash University animal ethics approvals (MARP 2012/158, MARP 2014/085, MARP 22185, and MARP 28911). All PDXs were previously established by the Melbourne Urological Research Alliance (MURAL) [22–25] and grown in male NSG mice. PDXs of castrate‐sensitive prostate cancer were grown in mice supplemented with 5‐mm testosterone implants, whereas PDXs of CRPC were grown in castrated host mice, as previously described [26–32].…”

Ribosome Biogenesis: A Central Player in Cancer Metastasis and Therapeutic Resistance

“…CX-5461 demonstrated clinical efficacy in AML and multiple myeloma ( 116–118 ) and showed a promising therapeutic effect in ovarian carcinomas by P53-independent initiation of DNA damage ( 119, 120 ). CX-5461 also sensitized homologous recombination (HR)-proficient castration-resistant prostate cancer (CRPC) to the PARP inhibitor talazoparib, synergistically inhibiting tumor growth in a preclinical CRPC PDX model ( 121 ).…”

Tumor organoids: applications in cancer modeling and potentials in precision medicine

“…Combination treatment with talazoparib (a PARP inhibitor) and CX-5461 (an inhibitor of RNA polymerase I transcription and an activator of the DNA damage response) might be a promising candidate treatment for HR-proficient patients who are not suitable for PARP inhibitor monotherapy, which was verified by increased DNA damage and decreased growth of organoids derived from HR-proficient castrate-resistant PC after treatment [177]. Based on tumoroids generated from circulating tumor cells of patients with HCC, oral cancer, or CRC, the Antrodia cinnamomea mycelium-derived bioactive compound GKB202 was indicated to be a promising adjuvant and enhancer for 5-FU-based treatment [178].…”